2-chloro substituted-4-azaphenothiazines



United States Patent 3,299,057 2-CHLOR0 SUBSTlTUTED-4-AZAPHENO- THIAZINES Albert Gross and Kurt Thiele, Frankfurt am Main, Ger-.

many, assignors to Deutsche Goldund Silber-Scheideanstalt vormals Roessler, Frankfurt am Main, Germany No Drawing. Filed Oct. 21, 1965, Ser. No. 500,167 Claims priority, application Germany, Apr. 13, 1962,

3 Claims. oi. zso z4s or, in other words, the two compounds -{3-[4-(2-hydroxyethyl) piperazino] propyl-(l)} 2-chloro-4-azaphenothiazine and 10-{3- [4-(2-acetoxyethyl) -piperazino] propyl-(1)}-2-chloro-4-azaphenothiazine and their pharmaceu'tically acceptable acid addition salts and quaternary ammonium salts and according to the invention it was found that these two compounds possess an unexpectedly high cataleptic action and sedative action as compared to previously known azaphenothiazines which do not have a chlorine atom in the 2-position and also as compared to other (not previously known) closely related compounds which do have a chlorine atom in the 2-position. The compounds in question have a strong neuroleptic action as well as a psychosedative action. Neuroleptics are pharmaceuticals used in the more radical psychic disturbances of the total complex of endogenic psychoses (mental illnesses such as schizophrenia, psychotic disturbances, such as delusions and hallucinations) and permit quieting of troubled mental patients or to free such patients from their mental delusions without causing the patients to fall asleep or to hold them in a type of continuous narcosis. A simultaneous sedative activity is a welcome supplemental action in the therapeutic application of a neuroleptic but is not a necessary requirement for such application. Psychosedatives influence states of fear, excitement and tension and can be useful in treatment of patients not mentally ill. In both neuroleptics and psychosedatives it is important that they do not impair consciousness, judgment and ability to think. In view of the very strong specific action of the compounds according to the invention, they are especially suited for use in therapy over long periods of time.

The following examples will illustrate the preparation of the compounds according to the invention.

Example 1.10-{3-[4(2-hydr0xyethyl)-piperazin0]- propyl-(l }-2-chl0r0-4-azaphenothiazine (a) 23.5 g. of 2-chloro-4-azaphenothiazine (prepared as described in application Serial No. 227,535, filed October 2, 1962), now U.S. Patent 3,200,116, dissolved in 150 ml. of toluene were reacted with 9.8 g. of a 50% sodium amide suspension in toluene while refluxing. Thereafter 16.3 g. of 2-piperazino-propyl chloride dissolved in 100 ml. of toluene were added dropwise while 3,299,057 Patented Jan. 17, 1967 continuing the refluxing. The mixture was stirred for a further two hours and subsequently washed twice with Water and shaken out with dilute HCl. The resulting aqueous solution was rendered alkaline with Na CO and extracted with benzene. The benzene solution was dried with K CO and evaporated to dryness, The residue was distilled under vacuum. 19.5 g. of the base, l0-[3-piperazino-propyl-(1)] 2-chloro-4 azaphenothiazine, with a boiling point of 245255 C. at 0.01 torr, were obtained. (b) 36 g. (0.1 mol) of the base as prepared under (a) dissolved in cc. of butanol were refluxed for 4 hours with 10 g. (0.125 mol) of ethylene chlorohydrin and 21 g. (0.15 mol) of potassium carbonate. The salts were then filtered ofi from the reaction mixture and the filtrate concentrated. The residue was distilled under vacuum. The resulting 4-hydroxy ethyl substituted piperazino compound of the formula above had a rboiling point of 275- 280 C. at 0.01 torr, The yield was 88% of theory.

Example 2.10-{3-[4-(2-acetoxyethyl)-piperazin0] p ropyl-(l }-2-chl0r0-4-azaphenothiazine 40.5 g. (0.1 mol) of the base prepared as in Example 1b were dissolved in 40 cc. of benzene and reacted at 40- 50 C. with 14 cc. (0.15 mol) acetic acid anhydride in the presence of 4 cc. of pyridine. The reaction mixture was allowed to stand for 24 hours and then rendered alkaline with Na CO The aqueous solution was extracted several times with benzene and the benzene solutions combined, dried with K CO and evaporated to dryness. 41 g. of the crude base were obtained which was converted to the dihydrochloride. 43 g. of the salt were obtained which after recrystallization from dimethylformamide-alcohol had a melting point of 245 C.

The following table compares the sedative activity, toxicities and cataleptic activities of the compounds according to the invention with corresponding azaphenothiazine compounds not substituted by chlorine, as well as of other 2-chloro substituted azaphenothiazines and their non-substituted counterparts.

The sedative activity was determined in a selenium cell apparatus after oral administration of the substances in question to mice and is expressed as ED 50 in mg./ kg.

The toxicities (LD 50 mg./kg.) were carried out on mice according to the method of Miller and Tainter upon intraperitoneal injection. The period of observation was 24 hours.

The cataleptic activity was determined on mice after intraperitoneal injection of the substance tested. The substance under investigation was administered in various logarithmically increasing doses and the catalepsy measured by the method described in Arzneimittelforschung 8, 489 (1958).

The compounds tested were as follows:

(a) 10-[3-dimethylamino-propyl-( 1)]-4- azaphenothiazine (a') the 2-chloro substituted counterpart (b) 10-[2-dimethylamino-propyl-(1) ]4- azaphenothiazine (b') the 2-chloro substituted counterpart (c) 10-[3-(4-methyl-piperazino)-propyl-(1) ]-4- azaphenothiazine (c) the 2-chl0ro substituted counterpart (d) 10- 3- (4-acetoxyethyl-homopiperazino -propyl- 1 ]-4-azaphenothiazine (d') the 2-chloro substituted counterpart (e) 10- 3- (4-hydroxyethyl-homopiperazino -propyl- 1) ]-4-azaphenothiazine (e') the 2-chloro substituted counterpart (f) 10- [3- (4-aoetoxyethyl-piperazino) -propyl- 1) ]-4-azaphenothiazine (f) the 2chloro substituted counterpart (g) 3- (4-hydroXyethyl-piperazino) -propyll ]-4-azaphenothiazine (g) the 2-chloro substituted counterpart sedative Toxicity Cataleptic activity Compound activity ED LB 50 mgJkg. ED 50 mgJkg.

mgJkg.

17. 3 115:1:11 16. 17 l18=l:6 7.83:5.4. =|=4 About 16. 17 665:4 8 (max. 20%). 107 174:1:8 l5:t2.8.

38 182i8 7.8i1.9. 6G ;}:8 40. 46 1155.:7 18.4=i=3.2. 45 222110 40. 22 154i6 16 (max. 10%). 16 148:1:7 19512.5. 3 161=|=l1 1.3:t0.4. l6 139:1;4 About 30.

4 We claim 1. An azaphenothi-azine compound of the formula /SITOI N N lHz-CHrCHrN N-Y wherein Y is selected from the group consisting of and 2. 10-{3-[4-(Z-hydroxyethyl)-piperazino] -propyll 2-chloro-4-azaphenothiazine.

*3. 10-{3- [4-(2-acetoxyethyl) piperazino] -propy1- 1 2-chloro-4-azaphenothiazine.

ReferencesCited by the Examiner FOREIGN PATENTS 840,892 7/ 1960 Great Britain. 893,284 4/1962 Great Britain. 654,426 12/ 1962 Canada.

JOHN D. RANDOLPH, Primary Examiner. 

1. AN AZAPHENOTHIAZINE COMPOUND OF THE FORMULA 